Astrocyte and vascular changes contribute to Alzheimer's disease
| dc.contributor.author | Li, Jiangtao | en |
| dc.contributor.committeechair | Olsen, Michelle Lynne | en |
| dc.contributor.committeemember | Sontheimer, Harald W. | en |
| dc.contributor.committeemember | Morton, Paul D. | en |
| dc.contributor.committeemember | Theus, Michelle Hedrick | en |
| dc.contributor.department | Genetics, Bioinformatics, and Computational Biology | en |
| dc.date.accessioned | 2024-12-20T09:00:16Z | en |
| dc.date.available | 2024-12-20T09:00:16Z | en |
| dc.date.issued | 2024-12-19 | en |
| dc.description.abstract | Alzheimer's disease (AD), the most prevalent age-related neurodegenerative disorder, is defined by the pathological accumulation of amyloid-β (Aβ) peptides, neurofibrillary tangles (NFTs), neuronal loss, and the activation of astrocytes and microglia. One of the early indicators of AD is a global reduction in cerebral blood flow (CBF), which precedes significant plaque formation and cognitive decline. This persistent decrease in CBF, along with diminished oxygen and glucose delivery to the brain, is thought to contribute to neurodegeneration, although the underlying mechanisms remain unclear. Astrocytes, critical regulators of both Aβ clearance and CBF, have garnered increasing attention in AD research. Astrocytes, one of the most abundant cell types in the central nervous system, play a vital role in maintaining overall brain health and function. In AD, astrocytes express key AD-related genes, including APP, PSEN1, PSEN2, and APOE. While astrocyte gene expression alterations have been observed, the relationship between these transcriptomic changes, protein expression, and cellular function requires further investigation. This dissertation examines astrocyte and vascular changes in AD using a well-described preclinical AD mouse model: hAPPJ20 mice. First, a multi-omics analysis of cortical astrocyte gene and protein expression was conducted at 3, 6, 12, and 18 months in female J20 and wild-type (WT) mice, revealing significant gene and protein expression differences linked to normal aging and AD progression. Several overlapping gene-protein pairs were identified as potential biomarkers for AD treatment and diagnosis. Gene Ontology analysis highlighted enriched pathways related to inflammation, disrupted metabolism, and vascular dysfunction starting at 6 months. Additionally, pathway analysis revealed apoptotic pathways were enriched in astrocytes isolated from diseased tissue. Further analysis revealed for the first time that astrocytes significantly decline by 12 months in the cortex and hippocampus of J20 AD-disease mice. Nest, we explored vascular network remodeling and amyloid-β (Aβ) accumulation in this same model. In male J20 mice, 40% of the total pial arterial Aβ accumulation was found in the meningeal vascular network by 12 months, while females showed around 20%. Aβ deposition was associated with increased vessel diameter and tortuosity of pial collateral vessels. AD mice also exhibited reduced blood flow in the cortical meningeal arteries and significant enlargement of pial collateral vessels compared to wild-type mice. | en |
| dc.description.abstractgeneral | Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder globally, characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), neuronal loss, and activation of glial cells. A global reduction in cerebral blood flow (CBF) is an early pathological feature of AD, occurring before significant plaque deposition and cognitive decline. Chronic reductions in CBF, along with decreased oxygen and glucose availability, are thought to contribute to neurodegeneration. Although the neurovascular hypothesis has been proposed to explain this phenomenon, the mechanisms underlying reduced CBF remain unclear. Astrocytes, among the most abundant cell types in the central nervous system (CNS), are essential for maintaining brain health. They express high levels of three key AD risk genes—APP, PSEN1, and PSEN2—and are the primary cell type expressing Apolipoprotein E (Apoe), a major risk factor for late-onset AD. Previous studies using sequencing approaches on astrocytes derived from AD tissue have revealed extensive gene expression changes linked to inflammation, cellular senescence, altered morphology, and changes in territory size. However, no study has yet compared these transcriptomic alterations to corresponding protein expression, leaving a critical gap in understanding astrocyte-related mechanisms in AD. In this dissertation, we investigated the contributions of astrocyte and vascular changes to AD using hAPPJ20 mice (J20 mice) as an AD animal model. We employed an unbiased multi-omics approach to analyze astrocyte transcriptome and proteome changes at 3, 6, 12, and 18 months in female J20 and wild-type (WT) mice. Our findings reveal significant age- and disease-related differences in astrocyte gene and protein expression, with these differences becoming more pronounced over time. By integrating differentially expressed genes and proteins, we identified several gene-protein pairs that may serve as potential predictive markers and diagnostic biomarkers at various stages of the disease. Gene Ontology (GO) enrichment analysis highlighted global inflammation, disrupted astrocyte metabolism, and vascular dysfunction emerging after the 6-month time point. Notably, apoptotic pathways were upregulated in female J20 mice compared to WT controls. Immunohistochemical analysis further demonstrated a significant reduction in astrocyte numbers in J20 mice by 12 months, providing additional evidence of astrocyte involvement in AD pathogenesis. Next, based on the vascular pathways dysfunction identified in our omics data, we also explored the pial artery/arteriole vascular network remodeling and brain vascular amyloid-β (Aβ) burden in J20 mice compared to WT mice. In our data, we found that almost 40% of the total pial arterial Aβ was accumulated in the meningeal vascular network in male J20 mice at 12 months old and around 20% for female J20 mice. Also, the vascular Aβ accumulation in pial arterial networks was related to increased diameter and tortuosity of pial collateral vessels. Significantly reduced overall blood flow was observed in cortical meningeal arterial network in AD mice compared to WT littermates. Furthermore, we also observed a significant enlargement of the pial collateral vessels in our AD mice models. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:42042 | en |
| dc.identifier.uri | https://hdl.handle.net/10919/123847 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | Astrocyte | en |
| dc.subject | vascular | en |
| dc.subject | Alzheimer's disease | en |
| dc.subject | transcriptome | en |
| dc.subject | proteome | en |
| dc.title | Astrocyte and vascular changes contribute to Alzheimer's disease | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Genetics, Bioinformatics, and Computational Biology | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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